Oral Presentation 10th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2025

P5-labeling for generating highly efficacious antibody-conjugates for cancer therapy (130584)

Christian E Stieger 1 2 , Marc-André Kasper 1 2 3 , Christian Hackenberger 1 2
  1. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
  2. Humboldt Universität zu Berlin, Berlin, Germany
  3. Tubulis GmbH, Planegg-Martinsried, Germany

Chemoselective or bioorthogonal reactions have revolutionized the molecular life sciences and enabled studying functional consequences of biological pathways and naturally occurring PTMs. Moreover, they enabled the generation of novel protein- and antibody-conjugates for pharmaceutical and medicinal applications.[1]

In this presentation, we will present the development of Cystein-selective P(V)-reagents including unsaturated phosphonamidates[2] and phosphinates.[3] We applied these reactions in a so-called P5-labeling protocol for the generation of new antibody-drug conjugates (ADCs).[4]

With these next-generation drug conjugates, we show an improved efficacy and superior stability compared to clinically approved cancer therapeutics on the market for the targeted delivery of pharmaceuticals. In addition, we utilize different thiol nucleophiles with attenuated nucleophilicity for orthogonal chemoselective bioconjugation schemes to obtain ADCs carrying two different cytotoxic payloads.[5] 

  1. a) D. Schumacher, C.P.R. Hackenberger, Curr. Opin. Chem. Biol. 2014, 22, 62-69; b) P. Ochtrop, C.P.R. Hackenberger, Curr. Opin. Chem. Biol. 2020, 58, 28-36.
  2. a) M.-A. Kasper et al., Angew. Chem. Int. Ed. 2019, 58, 11631-11636; b) M.-A. Kasper et al., Angew. Chem. Int. Ed. 2019, 58, 11625-11630; c) M.-A. Kasper et al., Chem Sci. 2019, 10, 6322-6329; d) Y. Park et al., Chem. Sci. 2021, 12, 8141-8148; e) P. Ochtrop et al., Chem Sci. 2023, 14, 2259-2266.
  3. a) C.E. Stieger et al., Angew. Chem. Int. Ed. 2021, 60, 15359-15364; b) C.E. Stieger et al., Angew. Chem. Int. Ed. 2022, 61, e202205348.
  4. a) M. Roas et al., Blood 2023, 141 (9), 1023–1035; b) S. Schmitt et al. Mol. Cancer Ther. 2024, 23, 199-211; c) M. Able et al., Leukemia, 2025, 39, 632-642. [5] M. A. R. de Geus et al., J. Am. Chem. Soc. 2025, 147, 18888-19000.